Summary Herpes zoster (HZ) is the consequence of the reactivation of varicella-zoster virus (VZV), latent in sensory neurons, that is not adequately controlled by ambient VZV-specific T cell immunity. These critical immune responses decline with age. Of the two available HZ vaccines, one (Zostavax; zoster vaccine live [ZVL]) is moderately efficacious (~50%), but efficacy is greatly influenced by the age of the vaccinee and efficacy wanes at 5-8 years; the other vaccine (Shingrix; adjuvanted recombinant glycoprotein E vaccine [SRX]) is ~90% effective, regardless of age at the time of administration, and to date has not waned. This proposal will define important differences in the immune response to each of the vaccines, and will investigate mechanisms that explain these differences. We are able to recruit participants who received each of these vaccines at least 5 years previously or in the past year, thus facilitating research on the difference in durability of the two vaccines. As a model of reactivation of VZV, we will challenge participants (note: humans are the only hosts in which VZV can be reliably studied) with intradermal VZV (the licensed vOka vaccine strain) and use as an outcome measure the presence of VZV nucleic acids in blood, which we previously showed occurred frequently after administration of this strain. This measure of viremia will be correlated with measures of VZV-specific immune responses that limit the replication of the live VZV challenge virus. These will include: 1) measures of local tissue (skin biopsy) responses using tissue imaging to detect VZV and the nature of the early infiltrating immune cell types; 2) early plasma and tissue biomarkers (cytokines and chemokines); 3) the phenotype of cell-mediated responses (T cells, NK, and antigen-presenting cell subsets); 4) transcriptomic analysis of early gene responses in skin and PBMC after the VZV challenge. This will be aided by our finding gE-specific epitopes for HLA class I and II alleles that will be used to prepare gE-specific tetramers. We will identify the components of the immune response to VZV challenge that are most likely to mediate the control of viral replication. We are interested in systemic markers, since blood is readily accessible and we seek immune correlates with control of viral replication that can be used in other studies. We are including local responses, because rapidity and success of immune control of viral replication at the site of inoculation (modelling the site of early replication of reactivated VZV) is crucial for HZ pathogenesis and vaccine-conferred protection. The last aim of this application is to analyze the relationship of the responses to SRX administration with the immune responses that reduce viremia after VZV challenge, especially the relationship between the magnitude of gE-memory T cell responses to SRX (which we previously showed was a marker of this superior HZ vaccine) and reduced viremia after VZV challenge.